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Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway.

Wang YJ, Li Q, Xiao HB, Li YJ, Yang Q, Kan XX, Chen Y, Liu XN, Weng XG, Chen X, Cai WY, Guo Y, Huang HF, Zhu XX - Drug Des Devel Ther (2015)

Bottom Line: First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26.Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells.In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Capital Medical University, Beijing, People's Republic of China.

ABSTRACT
Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.

No MeSH data available.


Related in: MedlinePlus

CHB exerts anti-MDR activity in vivo.Notes: (A, B) The xenograft experiment was carried out using nude mice implanted subcutaneously with KB or KBV200 cells under the right armpits. Data are mean ± SD of the relative tumor volume for each group of eight experimental animals. (C, D) The picture shows the tumor size of KB and KBV200 xenograft at the end of the experiment.Abbreviations: CTR, vehicle control group; CHB-L, 1 mg/kg group; CHB-H, 2 mg/kg group; VCR, vincrinstine group; CHB, chamaejasmin B; MDR, multidrug resistance; RTV, relative tumor volumes; SD, standard deviation.
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f2-dddt-9-5301: CHB exerts anti-MDR activity in vivo.Notes: (A, B) The xenograft experiment was carried out using nude mice implanted subcutaneously with KB or KBV200 cells under the right armpits. Data are mean ± SD of the relative tumor volume for each group of eight experimental animals. (C, D) The picture shows the tumor size of KB and KBV200 xenograft at the end of the experiment.Abbreviations: CTR, vehicle control group; CHB-L, 1 mg/kg group; CHB-H, 2 mg/kg group; VCR, vincrinstine group; CHB, chamaejasmin B; MDR, multidrug resistance; RTV, relative tumor volumes; SD, standard deviation.

Mentions: Based on anti-MDR activity in vitro, anti-MDR activity of CHB was further evaluated in vivo by establishing KB and KBV200 xenograft models. As shown in Figure 2 and Table 2, in VCR-treated KB xenograft model, the %T/C and IR were 23.67% and 71.21%, respectively, while in KBV200 xenograft model they were 74.75% and 27.29%, respectively. Thus it was implied that KBV200 xenograft model was resistant to VCR treatment. At the same time, both CHB-treated groups exhibited good anticancer activity in either KB or KBV200 xenograft model. Especially, in CHB-H group (2 mg/kg), the %T/C and IR in KB xenograft model were 36.44% and 65.06%, respectively, while in KBV200 xenograft model, they were 48.29% and 69.06%, respectively. Notably, CHB also exerted good anti-MDR effect in vivo.


Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway.

Wang YJ, Li Q, Xiao HB, Li YJ, Yang Q, Kan XX, Chen Y, Liu XN, Weng XG, Chen X, Cai WY, Guo Y, Huang HF, Zhu XX - Drug Des Devel Ther (2015)

CHB exerts anti-MDR activity in vivo.Notes: (A, B) The xenograft experiment was carried out using nude mice implanted subcutaneously with KB or KBV200 cells under the right armpits. Data are mean ± SD of the relative tumor volume for each group of eight experimental animals. (C, D) The picture shows the tumor size of KB and KBV200 xenograft at the end of the experiment.Abbreviations: CTR, vehicle control group; CHB-L, 1 mg/kg group; CHB-H, 2 mg/kg group; VCR, vincrinstine group; CHB, chamaejasmin B; MDR, multidrug resistance; RTV, relative tumor volumes; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590417&req=5

f2-dddt-9-5301: CHB exerts anti-MDR activity in vivo.Notes: (A, B) The xenograft experiment was carried out using nude mice implanted subcutaneously with KB or KBV200 cells under the right armpits. Data are mean ± SD of the relative tumor volume for each group of eight experimental animals. (C, D) The picture shows the tumor size of KB and KBV200 xenograft at the end of the experiment.Abbreviations: CTR, vehicle control group; CHB-L, 1 mg/kg group; CHB-H, 2 mg/kg group; VCR, vincrinstine group; CHB, chamaejasmin B; MDR, multidrug resistance; RTV, relative tumor volumes; SD, standard deviation.
Mentions: Based on anti-MDR activity in vitro, anti-MDR activity of CHB was further evaluated in vivo by establishing KB and KBV200 xenograft models. As shown in Figure 2 and Table 2, in VCR-treated KB xenograft model, the %T/C and IR were 23.67% and 71.21%, respectively, while in KBV200 xenograft model they were 74.75% and 27.29%, respectively. Thus it was implied that KBV200 xenograft model was resistant to VCR treatment. At the same time, both CHB-treated groups exhibited good anticancer activity in either KB or KBV200 xenograft model. Especially, in CHB-H group (2 mg/kg), the %T/C and IR in KB xenograft model were 36.44% and 65.06%, respectively, while in KBV200 xenograft model, they were 48.29% and 69.06%, respectively. Notably, CHB also exerted good anti-MDR effect in vivo.

Bottom Line: First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26.Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells.In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Capital Medical University, Beijing, People's Republic of China.

ABSTRACT
Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.

No MeSH data available.


Related in: MedlinePlus